Automatic metabolism modulator for glycolytic intervention-induced cascade cancer therapy

Abstract

Effective intervention in glycolytic metabolism is a promising way to inhibit tumor malignant invasion. However, the inherent hypoxia environment and unitary regulating model subsequently compromise its therapeutic efficacy. Herein, a facile way to design an automatic metabolism modulator (auto-MMOD) is developed by loading glucose oxidase (GOx) and DNA-templated silver nanoclusters (DNA-AgNCs) into a pH-responsive zeolitic imidazolate frameworks-8 (ZIF-8) nanocarrier, which can activate a cascaded metal ion-killing effect during GOx-regulated glycolysis metabolism. When the acidic lysosome microenvironment induces ZIF-8 decomposition, the released GOx can effectively consume glucose and generate H₂O₂, thus inhibiting Adenosine Triphosphate synthesis and accelerating tumor starvation. Moreover, the released Ag⁺ in response to H₂O₂ can disturb bioenergy metabolism to inhibit tumor proliferation, which further enhances the tumor-killing effect in hypoxic microenvironments. This study achieves effective tumor suppression in vitro and in vivo by integrating ion therapy into glycolysis intervention, which establish a promising strategy for nano-theranostics.